Through this application, The University of Texas MD Anderson Cancer Center seeks funding for renewal of its Prostate Cancer SPORE. This application is submitted under the Multiple Principal Investigator plan (MPI) by Principal Investigators Drs. Christopher J. Logothetis and Timothy C. Thompson, who are recognized internationally for their research in prostate cancer, The MD Anderson Prostate Cancer SPORE has created a stable and dynamic infrastructure for translational research to meet and successfully address specific challenges in reducing suffering and mortality rates for men with prostate cancer. We continue to build on our capacity to conduct novel, innovative clinical trials and believe that new research projects conducted by our translational research team will yield substantial progress and meaningful changes in clinical practice. In the current proposal, we define our translational research challenges and goals as (1) quantitative definition of prostate cancer risk to eliminate overtreatment of low-risk prostate cancer, (2) development of novel therapeutic approaches to overcoming resistance of castration-resistant prostate cancer (CRPC) to available therapies, and (3) development of novel alternative strategies for CRPC and treatment-refractory disease. We will achieve these translational research goals by identifying and testing novel predictive and prognostic biomarkers to determine the need for therapy in patients with early-stage prostate cancer, developing and testing novel immunotherapy for CRPC, developing and testing a novel approach to overcoming osteocrine- mediated resistance of bone metastasis to therapy, and developing and testing lead-in combination therapy to maximize DNA damage response-targeted therapy for CRPC. We will accomplish our goals via 4 research projects (including one population science research project), 3 support cores (Administrative, Biostatistics and Bioinformatics, and Biospecimen and Pathology), a dynamic Developmental Research Program, and an effective Career Enhancement Program. We are optimistic that our research efforts will contribute to reductions in the incidence, morbidity, and mortality of this devastating disease by translating basic research findings into clinical practice.